Natural immunity refers to the ability of pre-existing or rapidly- inducible host effector systems to combat infectious agents to which the host has not previously been immunized. Understanding how the natural immune system functions may provide us with strategies that would increase one's resistance to infectious agents and to tumor development. Natural killer (NK) cells are an important component of the this natural immune system, as they can mediate immunoregulatory functions and resistance to infections and tumor growth. My laboratory has shown that cytokines, most notably interferons (IFN), induced during viral infections elicit the activation and proliferation of natural killer (NK) cells, which infiltrate areas of virus-infected tissue. These NK cells are profound mediators of natural resistance against certain viruses, such as murine cytomegalovirus (MCMV), but not others, such as lymphocytic choriomeningitis virus (LCMV). Recently we have isolated NK- sensitive and -resistant variants of the arenavirus, Pichinde (PV), and have discovered that natural resistance to infection may also be mediated by T cells expressing gamma delta T cell receptors (TcR) and by remotely crossreactive memory alpha beta T cells specific for other viruses. The specific aims of this proposal are the following: 1. to examine the mechanism of the antiviral effect of NK cells in vivo; 2. to determine whether there are redundancies in the mechanisms of natural resistance to viruses; 3. to determine whether selected NK cell subsets have distinct antiviral activities; and 4. to do a molecular analysis of NK- sensitive and NK-resistant variants of PV, in order to determine which viral gene product confers the phenotype of NK-sensitivity.